DESCRIPTION (applicant's abstract): Many aspects of behavior and physiology, such as sleeping and wakefulness, blood pressure, and body temperature, exhibit daily oscillations known as circadian rhythms. Disturbances in these circadian rhythms are responsible for the debilitating effects of jet lag, shift work, and the sleep disorders commonly seen in patients suffering from Alzheimer's disease. Circadian rhythms are driven by an intrinsic biological clock found in organisms ranging from plants to humans. In mammals, this biological clock is housed in a small cluster of cells called the suprachiasmatic nucleus (SCN), buried deep within the brain. These intrinsic circadian rhythms are synchronized to the daily environmental cycle of day and night by the process of photoentrainment, which uses light information to reset the biological clock. In mammals, the neuronal signal for photoentrainment arises from a small subset of retinal ganglion cells (RGCs) that send a direct projection to the SCN. Surprisingly, the retinal pathways used to encode circadian information seem to be different from those used to encode visual information. In the classical view of the visual pathway, light is detected only by the rod and cone photoreceptors. However, these cells are not required for photoentrainment. The solution to this apparent paradox may lie in the recent discovery of a novel visual pigment, melanopsin, which is expressed in a subset of RGCs. These findings lead to the intriguing hypothesis that the RGCs projecting to the SCN express melanopsin and are intrinsically sensitive to light. To date, nothing is known about the physiology of the RGCs that provide retinal input to the circadian system. Recently, however, we have developed techniques that allow us to routinely identify and study these neurons in isolation. The primary objective of the proposed research is to study the properties of mammalian RGCs that project to the SCN using a combination of molecular genetic and electrophysiological techniques. Specifically, we will utilize patch-clamp techniques to examine the intrinsic membrane properties of these neurons. In addition, we will test their light-sensitivity, and use both RT-PCR and in situ hybridization to determine if they express melanopsin. The results will represent the first functional characterization of the neurons that convey the photoentrainment signal from the retina to the SCN. The knowledge gathered in this study will lay the foundation for improved light therapy and/or pharmacological treatment of circadian disorders that are often associated with Alzheimer's disease and are responsible for the debilitating effects of jet lag and shift work.